The myelodysplastic syndromes (MDS) represent a heterogeneous group of diseases that manifest themselves as dyspoiesis. Abnormal clonal development of hematopoietic progenitors in MDS leads to severe cytopenias and a predisposition to develop acute myelogenous leukemia. Current therapeutic options for MDS are limited, and aside from bone marrow transplantation, none have proven superior to supportive measures alone. Preclinical investigations have indicated a potential therapeutic role for vitamin D in treatment of MDS. However, because of dose-limiting toxicity of hypercalcemia, clinical trials with vitamin D have used low doses, with promising but inconsistent results. We have developed a dosing schema of Dexamethasone and calcitriol (the active form of vitamin D) that augments the therapeutic index of calcitriol, and allows for safe administration of 5-10 times higher doses of calcitriol than has previously been used for MDS. We have also determined that Dexamethasone potentiates the activity of vitamin D in a number of preclinical models for squamous cell carcinoma and prostate cancer. In this proposal we will test the hypothesis that the combination of Dex and high-dose calcitriol will be effective for treatment of MDS. We propose herein a phase II trial of Dex and calcitriol for MDS. This trial will analyze hematologic response and toxicity. Bone marrow samples will be serially analyzed for differentiation, cell cycle arrest, and apoptosis. The in vitro studies will be correlated with in vivo response. Our hope is that these studies will help us develop a potentially novel, oral, minimally toxic regimen for treating MDS.